The sodium new houttuyfonate suppresses NSCLC via activating pyroptosis through TCONS-14036/miR-1228-5p/PRKCDBP pathway.

Several studies have suggested the potential value of Houttuynia cordata as a therapeutic agent in lung cancer, but direct evidence is still lacking. The study aimed to determine the regulatory impact of a major H. cordata constituent derivative (sodium new houttuyfonate [SNH]) on lncRNA networks in non-small cell lung cancer (NSCLC) to identify new potential therapeutic targets. After exposing NSCLC cells to SNH, we analysed the following: cell death (via flow cytometry, TUNEL and ASC speck formation assays), immune factors (via ELISA), gene transcription (via RT-qPCR), subcellular localisation (via FISH), gene-gene and gene-protein interactions (via dual-luciferase reporter and RNA immunoprecipitation assays, respectively) and protein expression and distribution (via western blotting and immunocytochemistry or immunohistochemistry). In addition, statistical analysis (via one-way ANOVA or unpaired t-tests) was performed. Exposure to SNH promoted NSCLC cell pyroptosis, concomitant with significant up-regulation of TCONS-14036, a novel lncRNA. Mechanistic research demonstrated that TCONS-14036 functions as a competing endogenous (ce)RNA by sequestering microRNA (miR)-1228-5p, thereby up-regulating PRKCDBP-encoding transcript levels. Indeed, PRKCDBP promoted pyroptosis by activating the NLRP3 inflammasome, resulting in CASP1, IL-1ß and GSDMD cleavage. Our findings elucidate the potential molecular mechanisms underlying the ability of SNH to suppress NSCLC growth through activation of pyroptosis via the TCONS-14036/miR-1228-5p/PRKCDBP pathway. Thus, we identify a new potential therapeutic targets for NSCLC.

Gexia-Zhuyu Decoction Attenuates Carbon Tetrachloride-Induced Liver Fibrosis in Mice Partly via Liver Angiogenesis Mediated by Myeloid Cells.

BACKGROUND This study aims to demonstrate the underlying correlation between the resolution of liver fibrosis induced by Gexia-Zhuyu decoction (GZD) treatment and myeloid cell-mediated angiogenesis. MATERIAL AND METHODS A liver fibrosis mouse model induced by carbon tetrachloride (CCl4) intervention was employed in this study. Dynamics of blood liver function parameters were followed. The liver pathology was detected by Sirius Red and Masson staining. Matrix metalloproteinase (MMP) 2/9, tissue inhibitors of metalloproteinase (TIMP)-1/2, and vascular endothelial growth factor (VEGF)-A expression levels were measured. Bone marrow chimera mice were generated by transfer of bone morrow cells from green fluorescent protein (GFP)-knockin mice into irradiated wild-type mice, and were used it to visualize the role of myeloid cells on the fibrosis resolution induced by GZD treatment. RESULTS The result of Sirius Red and Masson staining and the dynamics of blood liver function parameters showed that 5 weeks of GZD treatment attenuated the severity of liver fibrosis with continual CCl4 administration. GZD treatment promoted the expression of MMP2/9 and repressed the heightened level of TIMP-1/2 in the recovery phase. More notably, the increased VEGF-A and augmented endothelial progenitor cells were observed in the liver and blood in mice that received GZD, and contributed to the remodeling of hepatic vascular though the CXCL12/CXCR4 axis. Then, chimera mice with GFP-positive bone marrow cells were used to show angiogenesis driven by GZD-induced myeloid cell motivation. We found that GZD facilitated myeloid cells binding to the vascular CXCR4 and induced the resolution of fibrosis. CONCLUSIONS This study shows that activation of myeloid cells induced by GZD administration accelerates the functional angiogenesis, which benefits the resolution of CCl4-induced liver fibrosis.

Inhibition of casein kinase 2 blocks G2/M transition in early embryo mitosis but not in oocyte meiosis in mouse.

Casein kinase 2 (CK2) is a highly conserved, ubiquitously expressed serine/threonine protein kinase with hundreds of substrates. The role of CK2 in the G2/M transition of oocytes, zygotes, and 2-cell embryos was studied in mouse by enzyme activity inhibition using the specific inhibitor 4, 5, 6, 7-tetrabromobenzotriazole (TBB). Zygotes and 2-cell embryos were arrested at G2 phase by TBB treatment, and DNA damage was increased in the female pronucleus of arrested zygotes. Further developmental ability of arrested zygotes was reduced, but that of arrested 2-cell embryos was not affected after releasing from inhibition. By contrast, the G2/M transition in oocytes was not affected by TBB. These results indicate that CK2 activity is essential for mitotic G2/M transition in early embryos but not for meiotic G2/M transition in oocytes.

AT7867 Inhibits Human Colorectal Cancer Cells via AKT-Dependent and AKT-Independent Mechanisms.

AKT is often hyper-activated in human colorectal cancers (CRC). This current study evaluated the potential anti-CRC activity by AT7867, a novel AKT and p70S6K1 (S6K1) dual inhibitor. We showed that AT7867 inhibited survival and proliferation of established (HT-29, HCT116 and DLD-1 lines) and primary human CRC cells. Meanwhile, it provoked caspase-dependent apoptosis in the CRC cells. Molecularly, AT7867 blocked AKT-S6K1 activation in CRC cells. Restoring AKT-S6K1 activation, via expression of a constitutively-active AKT1 ("ca-AKT1"), only partially attenuated AT7867-induced HT-29 cell death. Further studies demonstrated that AT7867 inhibited sphingosine kinase 1 (SphK1) activity to promote pro-apoptotic ceramide production in HT-29 cells. Such effects by AT7867 were independent of AKT inhibition. AT7867-indued ceramide production and subsequent HT-29 cell apoptosis were attenuated by co-treatment of sphingosine-1-phosphate (S1P), but were potentiated with the glucosylceramide synthase (GCS) inhibitor PDMP. In vivo, intraperitoneal injection of AT7867 inhibited HT-29 xenograft tumor growth in nude mice. AKT activation was also inhibited in AT7867-treated HT-29 tumors. Together, the preclinical results suggest that AT7867 inhibits CRC cells via AKT-dependent and -independent mechanisms.